Experiments are proposed to investigate the interaction between two risk factors for drug abuse: prenatal stress and being female. It is hypothesized that prenatal stress alters the neural systems that respond to novel situations differentially in males vs. females, but the consequences for both sexes is an enhanced response to cocaine which increases vulnerability for drug taking behavior. Prenatal stress exposes the developing organism to increased levels of glucocorticoids at a time during which critical growth is taking place so there are profound effects on the development of the nervous system and as a consequence the physiology and behavior of the adult offspring. Some of the consequences of prenatal stress include dysfunction of the stress axis, learning disabilities, depression, psychopathology and potentially an increased propensity to develop drug abuse. There are sex differences in drug abuse for many drugs of abuse, and even though there are more men with substance abuse disorders, the onset of addiction to cocaine is more rapid in women than in men. Women begin using cocaine at an earlier age, enter treatment at earlier ages and have developed more severe cocaine dependence at intake than men. In rats, female rats exhibit an enhanced behavioral sensitization to cocaine, they acquire cocaine self-administration more rapidly and at lower doses, and females exhibit greater motivation to take cocaine than do male rats. In results from pilot experiments we find in male rats that prenatal stress enhances behavioral sensitization following repeated cocaine, and acquisition of cocaine self-administration. In females, results of pilot experiments indicate that prenatal stress enhances the locomotor response to novelty, the acute response to cocaine, behavioral sensitization to cocaine, and the amount of cocaine taken on certain days of the estrous cycle. Thus, there is also increased risk for females after prenatal stress. Experiments proposed will test the hypothesis that prenatal stress increases vulnerability of males and females for the behavioral response to cocaine and cocaine self-administration via altered stress system-related gene expression and changes in dopamine function in the nucleus accumbens and striatum. The mechanisms mediating the effects of prenatal stress are hypothesized to be different for males vs. females, but the consequences for both sexes is an enhanced response to cocaine which increases vulnerability for drug taking behavior. Importantly, many of the effects of prenatal stress can be reversed by cross-fostering to non- stressed dams. Experiments will also investigate the extent that maternal behavior can ameliorate the effects of prenatal stress on stress system-related gene expression, change dopamine function in the nucleus accumbens and striatum and on drug taking behavior. PUBLIC HEALTH RELEVANCE: Why do some individuals start taking drugs of abuse? Experiments proposed will investigate what goes wrong in the brains of males and females as consequence of prenatal stress that may lead to addiction, and whether it is possible to compensate for these effects by changes in maternal behavior. Results from these experiments will have implications for treatment and prevention of drug abuse using non-pharmacological interventions.